Gab1 in livers with persistent hepatocyte apoptosis has an antiapoptotic effect and reduces chronic liver injury, fibrosis and tumorigenesis

2021 ◽  
Author(s):  
Tetsuo Takehara ◽  
Naoki Mizutani ◽  
Hayato Hikita ◽  
Yoshinobu Saito ◽  
Yuta Myojin ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Liver Injury ◽  
Cell Viability ◽  
Liver Regeneration ◽  
Adaptor Protein ◽  
Chronic Liver ◽  
Hepatocyte Apoptosis ◽  
Chronic Liver Injury ◽  
The Impact

Grb2-associated binder 1 (Gab1) is an adaptor protein that is important for intracellular signal transduction by receptor tyrosine kinases that are receptors for various growth factors and plays an important role in rapid liver regeneration after partial hepatectomy and during acute hepatitis. On the other hand, mild liver regeneration is induced in livers of individuals with chronic hepatitis, where hepatocyte apoptosis is persistent; however, the impact of Gab1 on such livers remains unclear. We examined the role of Gab1 in chronic hepatitis. Gab1 knockdown enhanced the decrease in cell viability and apoptosis induced by ABT-737, a Bcl-2/-xL/-w inhibitor, in BNL.CL2 cells, while cell viability and caspase activity were unchanged in the absence of ABT-737. ABT-737 treatment induced Gab1 cleavage to form p35-Gab1. p35-Gab1 was also detected in the livers of mice with hepatocyte-specific Mcl-1 knockout (KO), which causes persistent hepatocyte apoptosis. Gab1 deficiency exacerbated hepatocyte apoptosis in Mcl-1 KO mice with posttranscriptional downregulation of Bcl-XL. In BNL.CL2 cells treated with ABT-737, Gab1 knockdown posttranscriptionally suppressed Bcl-xL expression, and p35-Gab1 overexpression enhanced Bcl-xL expression. Gab1 deficiency in Mcl-1 KO mice activated STAT3 signaling in hepatocytes, increased hepatocyte proliferation, and increased the incidence of liver cancer with the exacerbation of liver fibrosis. In conclusion, Gab1 is cleaved in the presence of apoptotic stimuli and forms p35-Gab1 in hepatocytes. In chronic liver injury, the role of Gab1 in suppressing apoptosis and reducing liver damage, fibrosis, and tumorigenesis is more important than its role in liver regeneration.

1032 DISSECTING THE ROLE OF Chk2, p53 AND p21 FOR LIVER REGENERATION AND TUMOR DEVELOPMENT DURING CHRONIC LIVER INJURY

2013 ◽  
Vol 58 ◽  
pp. S424
Author(s):  
L. Buitrago-Molina ◽  
S. Marhenke ◽  
J. Orlik ◽  
T. Longerich ◽  
R. Geffers ◽  
...  
Keyword(s):  
Liver Injury ◽  
Liver Regeneration ◽  
Tumor Development ◽  
Chronic Liver ◽  
Chronic Liver Injury

Inhibition of monoacylglycerol lipase, an anti-inflammatory and antifibrogenic strategy in the liver

Gut ◽  
2018 ◽  
Vol 68 (3) ◽  
pp. 522-532 ◽  
Author(s):  
Aida Habib ◽  
Dina Chokr ◽  
JingHong Wan ◽  
Pushpa Hegde ◽  
Morgane Mabire ◽  
...  
Keyword(s):  
Liver Injury ◽  
Cannabinoid Receptor ◽  
Chronic Liver ◽  
Autophagic Flux ◽  
Monoacylglycerol Lipase ◽  
Chronic Liver Injury ◽  
Fibrosis Progression ◽  
Duct Ligation ◽  
Anti Inflammatory ◽  
The Impact

ObjectiveSustained inflammation originating from macrophages is a driving force of fibrosis progression and resolution. Monoacylglycerol lipase (MAGL) is the rate-limiting enzyme in the degradation of monoacylglycerols. It is a proinflammatory enzyme that metabolises 2-arachidonoylglycerol, an endocannabinoid receptor ligand, into arachidonic acid. Here, we investigated the impact of MAGL on inflammation and fibrosis during chronic liver injury.DesignC57BL/6J mice and mice with global invalidation of MAGL (MAGL-/-), or myeloid-specific deletion of either MAGL (MAGLMye-/-), ATG5 (ATGMye-/-) or CB2 (CB2Mye-/-), were used. Fibrosis was induced by repeated carbon tetrachloride (CCl4) injections or bile duct ligation (BDL). Studies were performed on peritoneal or bone marrow-derived macrophages and Kupffer cells.ResultsMAGL-/- or MAGLMye-/- mice exposed to CCl4 or subjected to BDL were more resistant to inflammation and fibrosis than wild-type counterparts. Therapeutic intervention with MJN110, an MAGL inhibitor, reduced hepatic macrophage number and inflammatory gene expression and slowed down fibrosis progression. MAGL inhibitors also accelerated fibrosis regression and increased Ly-6Clow macrophage number. Antifibrogenic effects exclusively relied on MAGL inhibition in macrophages, since MJN110 treatment of MAGLMye-/- BDL mice did not further decrease liver fibrosis. Cultured macrophages exposed to MJN110 or from MAGLMye-/- mice displayed reduced cytokine secretion. These effects were independent of the cannabinoid receptor 2, as they were preserved in CB2Mye-/- mice. They relied on macrophage autophagy, since anti-inflammatory and antifibrogenic effects of MJN110 were lost in ATG5Mye-/- BDL mice, and were associated with increased autophagic flux and autophagosome biosynthesis in macrophages when MAGL was pharmacologically or genetically inhibited.ConclusionMAGL is an immunometabolic target in the liver. MAGL inhibitors may show promising antifibrogenic effects during chronic liver injury.

scholarly journals Mechanisms of platelet-mediated liver regeneration

Blood ◽  
2016 ◽  
Vol 128 (5) ◽  
pp. 625-629 ◽  
Author(s):  
Ton Lisman ◽  
Robert J. Porte
Keyword(s):  
Liver Injury ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Therapeutic Strategies ◽  
Chronic Liver ◽  
Chronic Liver Injury ◽  
Multiple Functions ◽  
Definitive Evidence

Abstract Platelets have multiple functions beyond their roles in thrombosis and hemostasis. Platelets support liver regeneration, which is required after partial hepatectomy and acute or chronic liver injury. Although it is widely assumed that platelets stimulate liver regeneration by local excretion of mitogens stored within platelet granules, definitive evidence for this is lacking, and alternative mechanisms deserve consideration. In-depth knowledge of mechanisms of platelet-mediated liver regeneration may lead to new therapeutic strategies to treat patients with failing regenerative responses.

scholarly journals Persistent hepatocyte apoptosis promotes tumorigenesis from diethylnitrosamine-transformed hepatocytes through increased oxidative stress, independent of compensatory liver regeneration

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yasutoshi Nozaki ◽  
Hayato Hikita ◽  
Satoshi Tanaka ◽  
Kenji Fukumoto ◽  
Makiko Urabe ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hepatocellular Carcinoma ◽  
Chronic Hepatitis ◽  
Liver Regeneration ◽  
Liver Tumors ◽  
Tumor Formation ◽  
Transformed Cells ◽  
Wild Type ◽  
Hepatocyte Apoptosis ◽  
Chronic Liver Injury

AbstractHepatocellular carcinoma highly occurs in chronic hepatitis livers, where hepatocyte apoptosis is frequently detected. Apoptosis is a mechanism that eliminates mutated cells. Hepatocyte apoptosis induces compensatory liver regeneration, which is believed to contribute to tumor formation. Hepatocyte-specific Mcl-1 knockout mice (Mcl-1Δhep mice) developed persistent hepatocyte apoptosis and compensatory liver regeneration with increased oxidative stress in adulthood but had not yet developed hepatocyte apoptosis at the age of 2 weeks. When diethylnitrosamine (DEN) was administered to 2-week-old Mcl-1Δhep mice, multiple liver tumors were formed at 4 months, while wild-type mice did not develop any tumors. These tumors contained the B-Raf V637E mutation, indicating that DEN-initiated tumorigenesis was promoted by persistent hepatocyte apoptosis. When N-acetyl-L-cysteine was given from 6 weeks of age, DEN-administered Mcl-1Δhep mice had reduced oxidative stress and suppressed tumorigenesis in the liver but showed no changes in hepatocyte apoptosis or proliferation. In conclusion, enhanced tumor formation from DEN-transformed hepatocytes by persistent hepatocyte apoptosis is mediated by increased oxidative stress, independent of compensatory liver regeneration. For patients with livers harboring transformed cells, the control of oxidative stress may suppress hepatocarcinogenesis based on chronic liver injury.

scholarly journals The Role of PI3K p110gamma in chronic liver injury

2012 ◽  
Vol 50 (01) ◽  
Author(s):  
K Dostert ◽  
M Saugspier ◽  
C Dorn ◽  
C Hellerbrand ◽  
E Gäbele
Keyword(s):  
Liver Injury ◽  
Chronic Liver ◽  
Chronic Liver Injury

scholarly journals The role of Caspase‐1 in diet induced chronic liver injury and blood bile barrier regulation

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Tirthadipa Pradhan-Sundd ◽  
Shwetha Gudapati ◽  
Sean Brandon
Keyword(s):  
Liver Injury ◽  
Chronic Liver ◽  
Chronic Liver Injury ◽  
Caspase 1 ◽  
Barrier Regulation

scholarly journals MyD88-dependent signaling in non-parenchymal cells promotes liver carcinogenesis

2019 ◽  
Vol 41 (2) ◽  
pp. 171-181 ◽  
Author(s):  
Antje Mohs ◽  
Nadine Kuttkat ◽  
Tobias Otto ◽  
Sameh A Youssef ◽  
Alain De Bruin ◽  
...  
Keyword(s):  
Liver Injury ◽  
Disease Progression ◽  
Therapeutic Option ◽  
Intestinal Bacteria ◽  
Nuclear Factor Κb ◽  
Chronic Liver ◽  
Toll Like Receptors ◽  
Chronic Liver Injury ◽  
Liver Disease Progression ◽  
The Impact

Abstract In Western countries, a rising incidence of obesity and type 2 diabetes correlates with an increase of non-alcoholic steatohepatitis (NASH)—a major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). NASH is associated with chronic liver injury, triggering hepatocyte death and enhanced translocation of intestinal bacteria, leading to persistent liver inflammation through activation of Toll-like receptors and their adapter protein myeloid differentiation factor 88 (MyD88). Therefore, we investigated the role of MyD88 during progression from NASH to HCC using a mouse model of chronic liver injury (hepatocyte-specific deletion of nuclear factor κB essential modulator, Nemo; NemoΔhepa). NemoΔhepa; NemoΔhepa/MyD88−/− and NemoΔhepa/MyD88Δhepa were generated and the impact on liver disease progression was investigated. Ubiquitous MyD88 ablation (NemoΔhepa/MyD88−/−) aggravated the degree of liver damage, accompanied by an overall decrease in inflammation, whereas infiltrating macrophages and natural killer cells were elevated. At a later stage, MyD88 deficiency impaired HCC formation. In contrast, hepatocyte-specific MyD88 deletion (NemoΔhepa/MyD88Δhepa) did not affect disease progression. These results suggest that signaling of Toll-like receptors through MyD88 in non-parenchymal liver cells is required for carcinogenesis during chronic liver injury. Hence, blocking MyD88 signaling may offer a therapeutic option to prevent HCC formation in patients with NASH.

Sign in / Sign up

Export Citation Format

Share Document